Poor or limited drug solubility is one of the major challenges in oral drug delivery. It is well recognized that amorphization through molecular dispersion in a hydrophilic polymer (commonly known as amorphous solid dispersion) can increase the aqueous solubilities, dissolution rates, and possibly oral bioavailabilities of poorly water-soluble drugs. Despite the widely documented utility of this approach to resolving the solubility-related absorption issue of problematic drugs, the number of amorphous drug products that have successfully made their way to the market is still limited, which can be attributed to their inherently poor stability. Owing to their high free energy and thermodynamic activity, amorphous solids tend to revert back to their low-energy crystalline counterparts during storage, processing and/or dissolution, resulting in a complete loss of their unique advantage in solubility and bioavailability enhancement.
A review of the literature showed that most of the studies on amorphous solid dispersions focused on the characterization of drug-polymer miscibility, thermal properties, spectral characteristics, dissolution performance and physical stability under stressed conditions. Very few of these studies have attempted to elucidate the recrystallization behaviors of dispersed drugs in these systems. In addition, while the literature is replete with information on the solution-phase crystallization of drugs, very little is known about the solid-state crystallization behaviors of amorphous drugs in polymeric matrix, particularly for drugs capable of crystallizing into different polymorphs with different free energies and thermodynamic stabilities. Typically, upon recrystallization from the amorphous state, the relatively unstable polymorph will form first, as it is relatively close in free energy to the parent phase (Ostwald rule of stages). However, this unstable (metastable) polymorph will eventually revert to the stable form because of the associated favorable reduction in free energy. By elucidating the mechanisms of polymorph selectivity and establishing the conditions under which this occurs in the solid state, rational and effective strategies can be devised to control the formation of particular polymorph or to kinetically stabilize the solid drug in its amorphous form. The latter is commonly achieved by dispersing the drug in hydrophilic polymers as amorphous solid dispersions. Polymers can be selected based on their ability to inhibit the crystallization of the initially formed (unstable) polymorph, and the best polymer would be the one that exhibits the strongest crystal growth inhibition and offers the drug maximum physical stability.
Aimed at acquiring a mechanistic understanding of the crystallization behaviors and polymorph selectivity of amorphous drugs, the present study has employed itraconazole (ITZ) as a model compound. ITZ, a synthetic triazole antifungal agent, is a BCS II compound with extremely low water-solubility (1 ng/ml at pH 7.4), which may account for the relatively low oral bioavailability (˜55%) of its commercial product, Sporanox®. Moreover, ITZ has a relatively high glass transition temperature (Tg≈59° C.) and tends to form a fairly stable amorphous form through various processing treatments such as melt-quenching and lyophilization. Thus far, only one polymorph (Form I) has been reported in the literature. U.S. Application Publication No. 2003/0100568 documents the existence of a second polymorph (Form II). Although the physical stability of amorphous ITZ formulations has been extensively studied, none of these studies has delved into the polymorphic crystallization mechanism of pure amorphous ITZ, which may be important for successful development of stable ITZ solid dispersion systems.